Heart imaging with cationic complexes of technetium.

The cationic technetium-99 complex trans-[99TC(dmpe)2Cl2]+, where dmpe is bis(1,2-dimethylphosphino)ethane or (CH3)2P-CH2-P(CH3)2, has been prepared and characterized by single-crystal, x-ray structural analysis. The technetium-99m analog, trans-(99mTc(dmpe) 2Cl2]+, has also been prepared and shown to yield excellent gamma-ray images of the heart. The purposeful design, characterization, and synthesis of this technetium-99m radiopharmaceutical represents a striking application of fundamental inorganic chemistry to a problem in applied nuclear medicine.

Dosimetry of four heart-imaging radionuclides: 43K, 81Rb, 129Cs, and 201Ti.

In conjunction with research into the relative clinical suitability of radionuclides for heart imaging, estimates of the radiation dosimetry for 43K, 81Rb, 129Cs, and 201Tl were calculated. Estimates of absorbed radiation dose for the heart, kidneys, liver, lungs, testes, and whole body of the standard man were computed from published distribution data in rats via the MIRD method by assuming that the concentration in each organ per initial mean whole-body concentration is the same in rats and humans. The whole-body absorbed radiation doses from 81Rb, 129Cs, 201Tl, and 43K are 0.08, 0.17, 0.24, and 0.60 rads/mCi administered intravenously. In general, the organ doses from the four radionuclides follow the same order.

Cationic Tc-99m complexes as potential myocardial imaging agents.

Nineteen cationic Tc-99m complexes, based upon four different ligand series, have been synthesized under "no carrier added" conditions and qualitatively evaluated as myocardial imaging agents in a dog model. Of these complexes, the four halogen derivatives of the diars series [diars = o-phenylenebis(dimethylarsine)] successfully concentrate in the myocardium. These Tc-99m diars complexes are shown by thin-layer chromatography to be identical to the Tc-99 analogs that have been fully characterized as trans octahedral complexes of Tc(III) by classical chemical techniques. Tissue distribution studies in rats show a definite difference in the biodistributions of [99mTc(diars)2Cl2]+ and [99mTc(diars)2Br2]+, despite the similar size, shape, charge, and lipophilicity of these two complexes. A tissue distribution study in resting beagle dogs shows that [99mTc(diars)2Br2]+ accumulates in the normal myocardium about half as well as TI-201 (0.022 compared with 0.038% dose/g).

Intercomparison of myocardial imaging agents: 201Ti, 129Cs, 43K, and 81Rb.

Thallium-201, 129Cs, 43K, and 81Rb were evaluated as "static" myocardial-imaging agents. Optimal settings of the scintillation camera were determined for each agent. Accumulation for good-quality images can be started as early as 5 min after the dose with 43K, 10 min with 201T1, and 30 min with 129Cs. Imaging times were comparable for 43K, 129Cs, and 201T1 (using the 80-keV x-rays). High-energy photons from the 81Rb preparation, largely from 82mRb contaminant, made it impossible to obtain an interpretable image without the addition of more shielding. Absorbed radiation dose from 81Rb is lower than that from 43K, 129Cs, and 201T1. The highest background activity was observed with 81Rb, followed by 43K, 129Cs, and 201T1 in that order. Overall, 201T1 was best suited for imaging acute myocardial infarction with currently available equipment, and 129Cs was next best. However, because of instrument setting and commercially obtained preparations, 81Rb could not be properly compared with the other radionuclides in our study.

A comparison of technetium etidronate and pyrophosphate for acute myocardial infarct imaging.

Etidronate and pyrophosphate, labeled with Tc-95m and Tc-99m, were studied in experimentally infarcted mongrel dogs. A distribution study was conducted 2 hr after simultaneous administration of both agents in two groups of dogs. In one group, the injection was made 15 min after release of a 2-hr coronary arterial ligation. Another group was injected 48 hr after release of the ligation. The uptakes for each radiopharmaceutical and the ratio of uptakes for each sample were computed. The data show pyrophosphate to be a superior agent for the imaging of acute myocardial infarcts because of the higher uptake by infarcted myocardium and the greater contrast between infarcted myocardium and neighboring organs.

Cesium-129 myocardial scintigraphy to quantify myocardial infarction in dogs.

The sizes of surgically induced acute myocardial infarctions were quantified in a study of 28 dogs. Four projections (right and left anterior oblique, anterior, and left lateral) were obtained with 129Cs myocardial scintigraphy. Control images, taken before surgery, were compared with images taken 24-72 hr after coronary artery ligation. From postmortem examination the size of the infarct was determined and expressed as a percentage of the total left ventricle. On a standard diagram four independent observers marked the infarcted areas in each projection, expressed the severity of involvement in each area, and determined overall infarction size as a percentage of the total left ventricle. A nonlinear least-squares method was also employed to derive the size of the infarct, using the results from each observer's diagram. There were positive correlations between each observer's percentage estimate and the autopsy results. The overall accuracy of the least-squares method was similar to that of the individual observers. In this study, Observer 3 proved that acute myocardial infarcts can be quantified accurately from multiple scintigraphic projections of the myocardium, but the other three observers had difficulty in estimating infarct size. This difficulty probably resulted from the lack of well-validated criteria to aid the observer in determining the area of infarction, the severity of involvement within that area, or the total size of a myocardial infarct. Improvement in these estimates will require the development of definitive criteria, the use of optical scanners or computer processing, and combinations of radionuclides.

Collimator evaluation for Tl-201 myocardial imaging.

Three collimators--high-resolutions, converging, and pinhole--were evaluated for Tl-201 myocardial imaging. Line spread function, sensitivity measurements, and phantom and animal studies were used. Features common to all the collimators were: a) better resolution at a closer distance with higher count density, and b) higher infarct detection rate in the tangenital projection than in the en face view relative to the lesion. Furthermore, an infarct in the epicardial location was better visualized than one in the endocardial location. In terms of resolution and sensitivity, the high-resolution collimator was found to be satisfactory in most clinical imagings, but for visualization of an infarct, its size by weight must be over 10--12 g. The pinhole collimator could resolve an infarct as small as 7 g, and use of the pinhole yielded a diagnostic accuracy of over 90%, compared with 75-80% for the high-resolution collimator. Although the low sensitivity of the pinhole collimator precludes its routine clinical use, the selected view would increase diagnostic accuracy. The converging collimator performed poorly in terms of lesion detectability, and its routine clinical use is not encouraged. The conclusion drawn here is valid in the system we have studied, but the variety of converging collimators must be evaluated further for their specific purposes.

Effect of coronary blood flow on uptake and washout of Tc-99m DMPE and Tl-201.

After intravenous administration of Tc-99m DMPE the flow-dependent kinetics were studied in dogs during induced ischemia and during induced maximal reactive hyperemia. A control group was also studied. Mean time-activity curves obtained from the myocardial wall were compared within the same intervention group and also with other groups. During reactive hyperemia, there was a rapid and absolute increase in uptake followed by a rapid washout, whereas during ischemia there was a slow and decreased uptake followed by a slow washout. The magnitude of Tc-99m DMPE uptake during reactive hyperemia was slightly less than that of Tl-201, but the decreased uptake with ischemia was about equal for the two agents. Following maximal uptake in the myocardium the effective half-life of Tc-99m DMPE was one-third to one-fourth that of Tl-201. The similar kinetics of Tc-99m DMPE compared to Tl-201 suggests its usefulness in the evaluation of ischemic heart disease.

Basal kinetic studies of Tc-99m DMPE as a myocardial imaging agent in the dog.

Newly synthesized Tc-99m dichlorobis(1,2-dimethylphosphino)ethane (DMPE) was investigated as a myocardial imaging agent with respect to its kinetics (dependent on both time and regional coronary blood flow), its percent organ uptake, and its imaging characteristics in the anesthetized dog. Most of these data are compared with those of Tl-201. Blood clearance of the two agents is essentially the same. Compared with Tl-201, Tc-99m DMPE shows faster overall kinetics, higher heart-to-lung ratio, equally good correlation with a wide range of regional blood flows, and higher liver uptake. At the time of peak myocardial uptake, the mean heart uptake of Tl-201 is 4.3%, compared with 2.9% for Tc-99m DMPE, yet only 0.9% uptake of Tc-99m DMPE is found in the lung as compared with 3.3% for Tl-201. These differences result in a heart-to-lung ratio of 2:1 for Tc-99m DMPE and 1:1 for Tl-201, based on the data obtained from the time-activity curve. The quantitative findings are supported by the superior quality of Tc-99m DMPE images of both normal and infarcted dog heart. The high hepatic uptake of Tc-99m DMPE is not a serious problem if images are obtained within 5-60 min after dose. These basic kinetic studies suggest that Tc-99m DMPE is a promising myocardial imaging agent.

Effects of myocardial hypoxia and ischemia on myocardial scintigraphy.

The effect of regional myocardial ischemia and hypoxia on myocardial scintigraphy was studied in patients and dogs after intravenous administration of cesium-129. Seven men with angiographically proved ischemic heart disease underwent exercise testing and 129Cs was given immediately when ischemia was manifested in the electrocardiogram. Defects were not evident in the scintigrams of any patient. Failure to visualize a defect might be related to delayed uptake of 129Cs by the myocardium (maximal uptake in 45 minutes). The ischemic state was dissipated before the disparity in uptake between normal and ischemic myocardium could be visualized. Cesium-129 is useful for identifying acute myocardial infarcts but should not be used to visualize transient exercise-induced regional ischemia. Six dogs were given 129Cs after induction of regional myocardial hypoxia by perfusion of the anterior descending coronary artery with venous blood. In each, scintigraphy revealed a defect that resolved after reperfusion with arterial blood. Two other dogs were given 129Cs before perfusion with hypoxemic blood; neither dog manifested a defect. Since perfusion was maintained by a pump these results suggest that the major cause of the scintigraphically observed defect was inadequate cellular uptake of 129Cs rather than excessive cellular loss. Since regional myocardial hypoxia produced a reversible defect, scintigraphic studies might overestimate the size of an acute myocardial infarct in man by including the ischemic zone surrounding the infarct.

Radiotherapeutic agents: properties, dosimetry, and radiobiologic considerations.

Radioactive nuclides for treatment have occupied an important but somewhat diminishing role in the total practice of nuclear medicine. Although theoretically they should have important potentialities, particularly in the treatment of various forms of cancer, their development in this field has not kept pace with the progress in other treatment modalities in radiation oncology. Indications for the selection of appropriate isotopes for therapy revolve about the emission of beta particles of sufficient energy, which are administered in a chemical form that reaches the tumor. Methods of calculation of doses delivered to sites of deposition are discussed in the text. Radiobiologic considerations include the possibility of early deleterious effects from overdosage, and consideration of chromosomal changes of circulating lymphocytes and their implications. Late effects that have been of great public concern are confined almost solely to possible carcinogenesis, and this effect has been minimal in patients receiving therapeutic levels of radioactive drugs. Genetic and developmental effects, also, have been negligible. Complications encountered more frequently have been leukemia after extensive therapy of thyroid carcinoma, and local fibrosis after direct injection of radioactive colloids into tumor tissue.

Absorbed dose comparison: positron emitters 11C, 13N, and 15O versus gamma-ray emitters.

Absorbed doses were calculated or taken from the literature for various compounds of 11C, 13N, and 15O, and compared to those of presently gamma-ray-emitting nuclear medicine radiopharmaceuticals. As a rule of thumb, the doses per millicurie of the injectable positron-emitting compounds are of the same order of magnitude as the dose per millicurie of 99mTc compounds. The absorbed doses from the injectable positron emitters are nearly one or more orders of magnitude lower on a per millicurie basis than those from the other injectable gamma emitters that were investigated.

Measurements of the distribution of technetium-99m sulfur colloid and technetium-99m HEDP in normal humans.

Technetium-99m sulfur colloid and technetium-99m hydroxyethylidene diphosphonate (HEDP) are two radiopharmaceuticals that have been widely used in nuclear medicine. Radiation dose estimates for both materials have been published in the literature and are found in the package inserts of the commercial kits. However, these estimates were made without the benefit of quantitative human organ uptake data. Estimates of absorbed radiation dose to the kidneys differ by nearly a factor of 6 between the two calculations for HEDP. The results of this study are in agreement with the lower previous estimate. Other than that one exception, agreement of the previous estimates with the measurements reported here is surprisingly good.